The present invention relates to a novel process for producing a 4-halogeno-2-alkoxyimino-3-oxo fatty acid which is useful as an intermediate for synthesizing a cephalosporin antibiotic.
4-Halogeno-2-alkoxyimino-3-oxo fatty acids are important intermediates used for introducing an acyl group into the amino group at the 7-position of a cephalosporin antibiotic.
For example, 2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl group now used as main modifying group is introduced mainly by the two methods described below, in both of which 4-halogeno-2-methoxyimino-3-oxobutyric acid is used as an intermediate. A first method comprises synthesizing 2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetic acid by ring closure reaction of 4-halogeno-2-methoxyimino-3-oxobutyric acid with thiourea, protecting its amino group, converting the thus obtained compound into a reactive derivative such as acid chloride, and forming an amide linkage between the derivative and the amino group at the 7-position of a cephalosporin nucleus (Japanese Patent Appln. Kokai (Laid-Open) No. 53-103493). In a second method, the order of ring closure reaction and conversion to amide is reversed. That is, the second method comprises converting the amino group at the 7-position of a cephalosporin nucleus into an amide previously by use of a reactive derivative of 4-halogeno-2-methoxyimino-3-oxobutyric acid, and acting thiourea on the thus obtained compound to carry out ring closure reaction (Japanese Patent Appln. Kokai (Laid-Open) Nos. 54-98795 and 61-143389).
In addition, 2-(2-hydroxy-1,3-thiazol-4-yl)-2-methoxyiminoacetyl group obtained by converting the amino group of the above 2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl group is also used as a group for modifying cephalosporin antibiotics. Also in this case, 4-halogeno-2-methoxyimino-3-oxobutyric acid is used as an intermediate in the same manner as described above, except for acting a thiocarbamic acid ester in place of thiourea.
The 4-halogeno-2-alkoxyimino-3-oxo fatty acids are thus very important intermediates for producing cephalosporin antibiotics, but their production processes should be improved in many respects.
For example, Japanese Patent Appln. Kokai (Laid-Open) No. 54-98795 has disclosed a process for synthesizing 4-bromo-2-methoxyimino-3-oxobutyric acid which comprises direct bromination of 2-methoxyimino-3-oxobutyric acid. Since the starting material i.e., 2-methoxyimino-3-oxobutyric acid is obtained usually in the form of methyl ester or ethyl ester, the methyl or ethyl ester should be hydrolyzed by use of an alkali hydroxide before the bromination reaction, and therefore troublesome operations are required. Moreover, unlike the desired compound 4-bromo-2-methoxyimino-3-oxobutyric acid, 2-methoxyimino-3-oxobutyric acid is not stable in the form of a free acid and hence is susceptible to various decompositions during the ester decomposition reaction or a subsequent isolation procedure. Therefore, it is difficult to obtain 4-bromo-2-methoxyimino-3-oxobutyric acid of high purity in high yield.
On the other hand, as to the latter problem between the above problems, Japanese Patent Appln. Kokai (Laid-Open) No. 56-145290 has disclosed, as a process in which the decompositions of 2-methoxyimino-3-oxobutyric acid are prevented, a process which comprises subjecting tert-butyl ester of 2-methoxyimino-3-oxobutyric acid to ester decomposition in trifluoroacetic acid to obtain free acid, distilling off the trifluoroacetic acid, thereafter reacting bromine with the free acid in acetic acid and hydrobromic acid, and thereby producing 4-bromo-2-methoxyimino-3-oxobutyric acid. In this process, excessive decomposition of 2-methoxyimino-3-oxobutyric acid by water is prevented by obtaining the free acid without hydrolysis by taking advantage of the fact that under acidic conditions, the tert-butyl group of the tert-butyl ester is liberated as isobutylene. This process, however, is disadvantageous, for example, in that it uses trifluoroacetic acid which is highly toxic and corrosive, and that unstable 2-methoxyimino-3-oxobutyric acid should be heat-treated for distilling off the trifluoroacetic acid. Furthermore, this process is not yet free from troublesome operations.